Transient silencing of spinal nociceptive neurons leads to a long-term reduction in joint pain mediated by recruitment of opioid activity.

Chronic inflammatory joint pain remains inadequately treated despite current therapies, creating urgent clinical need for non-addictive alternatives in an era of heightened opioid-related concerns. A promising new approach involves conjugates of botulinum toxin and substance P (SP-BOT), which, when infused locally or spinally, have been shown to produce temporary pain relief in neuropathic mouse models, with its effects declining after approximately 100 days as the construct loses activity. However, its long-term efficacy in inflammatory pain models was unknown. Unexpectedly, in a mouse model of ankle inflammatory arthritis, a single intrathecal injection of SP-BOT at the peak of pain sensitivity produced a persistent reduction in mechanical hyperalgesia that lasted for weeks beyond the loss of construct activity. Furthermore, this late-phase pain relief exhibited a striking mechanism in that a single injection of the opioid antagonist naltrexone partially reversed the anti-hyperalgesia generated by SP-BOT. These data indicate that SP-BOT-mediated neuronal silencing initiates two distinct phases of pain relief. An initial, direct phase is followed by a second, sustained phase that maintains pain alleviation and is driven by endogenous opioid mechanisms.